The precise role of adrenergic mechanisms in the integration of metabolic physiology remains to be defined and definition of the role of adrenergic mechanisms in the pathophysiology of human disease has only recently begun. The objectives of the proposed studies are: 1) to develop a systematic approach to the study of sympathetic neural and adrenomedullary activity and catecholamine action in human subjects (with measurements of norepinephrine and epinephrine release employing isotope derivative and HPLC-ECD methods, plasma catecholamine kinetics, catecholamine plasma concentration-metabolic dose-response curves from graded, continuous infusions and alpha- and beta-adrenergic receptor status with radioligand displacement techniques) and to apply this approach to the study of human diseases such as diabetes mellitus, hypoglycemia, smoking associated acute coronary heart disease events and essential hypertension and to the phenomenon of aging; 2) to dissect the physiologic mechanisms of non-hypoglycemic glucose counter-regulation in man (?insulin, ?counter-regulatory hormones such as glucagon, epinephrine cortisol or growth hormone or neurotransmitter norepinephrine, ?glucose autoregulation, ?gut factors) with studies of the temporal patterns, of the effect of selective deficiencies of hormonal secretion or action (somatostatin, adrenergic blockade, epinephrine deficiency) and of hormonal replacement (glucagon, epinephrine) during non-hypoglycemic glucose counter regulation after i.v. glucose, oral glucose and simulated oral glucose employing stable isotope GC-MS glucose kinetics, the Biostator and operational microfluorometric, displacement and isotope derivative techniques preparative to the study of hypoglycemic mechanisms in patients including diabetics, and, potentially, of "open loop" insulin treatment of diabetes; and 3) to study organ specific norepinephrine turnover (heart, liver, pancreatic islets), coupled with plasma catecholamine levels, an index of sympathoadrenal activity, in rats, initially in response to defined metabolic (hypoglycemia, 2-deoxyglucose cellular "glucopenia") and hemodynamic stimuli preparative to the study of animal models of pathophysiologic states such as diabetes.